Kem F. Phillips

Pregabalin for Postherpetic Neuralgia: Placebo-Controlled Trial of Fixed and Flexible Dosing Regimens on Allodynia and Time to Onset of Pain Relief

UNLABELLED Time to onset of pain relief and improvement in allodynia in 269 patients with postherpetic neuralgia was examined in a 4-week randomized trial comparing flexibly dosed pregabalin (150-600 mg/d), fixed-dose pregabalin (300 mg/d), and placebo. For each patient with clinically meaningful pain reduction (>or=30%) at end point, onset of pain relief was defined as the first study day on which a patient reported >or=1-point reduction in pain relative to baseline. Average dose achieved was 396 mg/d in the flexible-dose group compared with 295 mg/d in the fixed-dose group. Median pain relief onset times were 3.5 days (flexible-dose), 1.5 days (fixed-dose), and >4 weeks (placebo). Compared with placebo, significantly more patients in both pregabalin treatment groups achieved >or=30% and >or=50% pain reduction at end point. Almost 95% of patients had brush-evoked allodynia, with 68% having moderate to severe allodynia (>or=40/100 mm). At baseline, pain and allodynia were highly correlated. Independent of treatment assignment, improvement in pain and improvement in allodynia were significantly correlated. Allodynia could serve as a useful surrogate outcome measure in future studies. Pregabalin was significantly better than placebo in alleviating allodynia (flexible-dose reduction, 26 mm; fixed-dose, 21 mm; placebo, 12 mm). Discontinuation rates due to adverse events were more frequent in the fixed-dose group. PERSPECTIVE A flexible-dose regimen reduces discontinuations, facilitates higher final doses, and results in a slightly greater pain relief. Allodynia (touch-evoked pain) can be of disabling severity and is present in nearly all patients with postherpetic neuralgia. Allodynia severity is correlated with pain severity and improvement in allodynia is correlated with clinical response.

The efficacy and safety of pregabalin in the treatment of neuropathic pain associated with chronic lumbosacral radiculopathy

&NA; We evaluated the efficacy of pregabalin in patients with chronic lumbosacral radiculopathy. This randomized, controlled, withdrawal trial included five phases: screening (4–18 days); run‐in (4–10 days) to screen out placebo responders; single‐blind (28 days) to identify pregabalin responders; double‐blind to randomize responders to pregabalin or placebo (35 days); and final study medication taper (7 days). The primary endpoint was time to loss of response (LOR) during the double‐blind phase (≥1‐point increase in pain, discontinuation, or rescue‐medication use). In the single‐blind phase, 58% of patients had ≥30% pain reduction. In the double‐blind phase, pregabalin (n = 110) and placebo (n = 107) groups did not differ significantly in time to LOR. Adverse events caused the discontinuation of 9.9% and 5.6% of pregabalin‐treated and placebo‐treated patients, respectively. Most patients with chronic lumbosacral radiculopathy responded to pregabalin therapy; however, time to LOR did not significantly differ between pregabalin and placebo. Considering the results of all phases of the study, it is difficult to draw definitive conclusions from it, suggesting a need for further work to understand the clinical potential of pregabalin treatment for lumbosacral radiculopathy.

Power of the two one-sided tests procedure in bioequivalence.

The power of the two one-sided tests procedure for testing bioequivalence is derived from the bivariate noncentral tdistribution. Power curves are shown and their use in planning bioequivalence experiments discussed. Sample sizes computed in the usual manner from an analysis of variance are shown to be too small to assure a declaration of bioequivalence except under favorable conditions.

Placebo-controlled, multicenter study of sertraline treatment for obsessive-compulsive disorder

The safety and efficacy of sertraline versus placebo were examined in a group of nondepressed outpatients with obsessive-compulsive disorder (OCD). Patients with moderate-to-severe OCD were recruited at 10 sites. After a 1-week placebo lead-in, patients were treated in a double-blind fashion for 12 weeks with sertraline or placebo. Sertraline was administered at a starting dose of 50 mg/day, with flexible titration up to 200 mg/day. The efficacy measures were the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH), and the Clinical Global Impression Scale (CGI) Severity of Illness and Improvement subscales. One hundred sixty-seven patients were randomly assigned and received at least one dose of double-blind medication: 86 received sertraline and 81 received placebo. All efficacy measures showed significantly greater improvement in the sertraline group from the end of week 8 until the end of week 12. Significantly greater improvement (p < 0.05) in the sertraline group first became apparent by the end of week 3 on the Y-BOCS and the CGI Improvement scale, and by the end of weeks 6 and 8, respectively, on the NIMH and CGI Severity scale. Sertraline was well tolerated, without serious adverse effects. In conclusion, sertraline was safe and effective in the treatment of patients with OCD.

Effect of Time of Administration on the Pharmacokinetics and Tolerance of Doxazosin in Healthy Male Volunteers

A randomized, open‐label, two‐way crossover study of 24 normotensive, healthy male volunteers with nocturia was conducted to compare morning and evening administration of doxazosin in terms of pharmacokinetics and tolerance. In both the morning and evening phases, participants received doxazosin 1 mg once daily for 10 days, followed by 2 mg once daily for 5 days. Pharmacokinetic data were evaluated from blood samples serially collected for 72 hours after drug administration on the last day of each phase. Vital signs and adverse events were recorded throughout the study. Mean peak plasma concentrations (Cmax) were 16.98 and 15.76 ng/mL after morning and evening administration, respectively. Corresponding mean values of area under the plasma concentration‐time curve (AUC0–24) were 227.90 and 253.66 ng.hr/mL, respectively. Statistical analysis of the log‐transformed values for Cmax and AUC0–24 indicated that morning and evening administration of doxazosin were bioequivalent. There were no statistically or clinically significant differences between phases for mean apparent half‐life (t1/2) or total body clearance. There were no clinically relevant differences in blood pressure or in pulse rate between phases, and no occurrences of orthostatic hypotension. The incidence of adverse experiences during morning and evening administration was similar. Morning and evening administration of doxazosin are equivalent and have similar tolerance profiles.

A log-normal model for individual bioequivalence

A log-normal model is developed for testing pi 1, the probability that a subjects response will fall within given bioequivalence limits. The model is a parametric analog of Anderson and Haucks TIER rule. Confidence intervals and hypothesis tests are derived. Statistical power is compared with the that of the TIER rule. The probability of demonstrating mean bioequivalence is shown to greatly exceed that of showing individual bioequivalence.

258 A DOUBLE‐BLIND, RANDOMIZED, PLACEBO‐CONTROLLED TRIAL TO EVALUATE TIME‐TO‐ONSET OF CLINICALLY MEANINGFUL PAIN RELIEF IN POSTHERPETIC NEURALGIA (PHN) PATIENTS TREATED WITH PREGABALIN

258 A DOUBLE-BLIND, RANDOMIZED, PLACEBOCONTROLLED TRIAL TO EVALUATE TIME-TOONSET OF CLINICALLY MEANINGFUL PAIN RELIEF IN POSTHERPETIC NEURALGIA (PHN) PATIENTS TREATED WITH PREGABALIN M.C. Rowbotham , B.R. Stacey , K. Phillips , E. Whalen , T.K. Murphy , J.A. Barrett * a UCSF Pain Clinical Research Center, San Francisco, CA,USA b Oregon Health & Science University, Portland, OR, USA c Pfizer, Inc., New York, USA

Testing microbiologic response to antiinfective medications with incomplete data.

Clinical trials of antiinfective medications often require estimates of the proportions of patients, Π, who are free of disease-causing pathogens at the end of treatment, as well as the proportions of all pathogens that have been eradicated. Each patient is infected with several species of pathogens, but the response to study medication for some of these pathogens may be unknown because some specimens were lost or because the patient received nonstudy medication that was known to be effective against these species. This paper develops a statistical model that estimates Π for each treatment and that accounts for the unknown pathogen responses as well as overdispersion of the remaining responses due to within-patient effects. The data are modeled with the Poisson distribution for the numbers of pathogen species per patient and the beta-binomial model for pathogen eradication. The Poisson and beta-binomial parameters are estimated through maximum likelihood estimation, and the treatment difference in the Π valves and its standard error are estimated by transforming the underlying parameters. Confidence intervals based on these estimates are constructed to test the hypothesis of noninferiority of the test treatment.